Transcript of “Which Type of Chemo Is Best When Facing a Radical Cystectomy? with Dr. Matthew Galsky”

October 6, 2023

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Voice over:

This is Bladder Cancer Matters, the podcast for bladder cancer patients, caregivers, advocates, and medical and research professionals. It’s brought to you by the Bladder Cancer Advocacy Network, otherwise known as BCAN. BCAN works to increase public awareness about bladder cancer, advances bladder cancer research, and provides educational and support services for bladder cancer patients and their loved ones. To learn more, please visit bcan.org.

Rick Bangs:

Hi, I’m Rick Bangs, the host of Bladder Cancer Matters, a podcast for, by and about the bladder cancer community. I’m also a survivor of muscle invasive bladder cancer, the proud owner of a 2006 model year neobladder and a patient advocate supporting cancer research at the Bladder Cancer Advocacy Network, or as many call it BCAN, producers of this podcast. I’m pleased to welcome today’s guest, Dr. Matt Galsky. Dr. Galsky is a medical oncologist focused on the care of patients with bladder cancer. He received his medical degree from Tufts University School of Medicine and subsequently completed training in internal medicine at Beth Israel Deaconess Medical Center, Harvard Medical School. He completed medical oncology fellowship at Memorial Sloan Kettering Cancer Center where he served as Chief Fellow.

In 2010, he joined the Tisch Cancer Institute, Mount Sinai School of Medicine as director of Genitourinary Medical Oncology, where he’s currently a professor of medicine. Dr. Galsky’s research has focused on the clinical development of novel therapies for bladder cancer, dissecting the clinical basis for heterogeneity and patient outcomes, and understanding the disconnect between the efficacy and effectiveness of available treatments. His current research extends beyond these efforts with a focus on immunotherapeutic approaches. And in addition, he is also a member of the BCAN Scientific Advisory Board. Dr. Galsky, thanks for joining our podcast.

Dr. Matthew Galsky:

Thank you. Glad to be here.

Rick Bangs:

So for many years I’ve heard doctors talk about the two major chemotherapy drugs for muscle invasive bladder cancer. Those would be MVAC and gemcitabine cisplatin, which is also called GemCis, and they kind of talked about them as if they were equal, although each had its fans. So I was pleased to hear that there was a clinical trial, it was called VESPER, and that’s spelled V-E-S-P-E-R. And it recently reported a head-to-head comparison between the two. So can you tell us about the VESPER trial and what its aims were?

Dr. Matthew Galsky:

So the VESPER study was a phase three study that was conducted in France, and it was an investigator initiated study. So this was a study developed by French oncologists really seeking to address an important question in the field. Which is that when chemotherapy is given before cystectomy and that chemotherapy is called neoadjuvant chemotherapy when it’s administered before cystectomy. Which treatment regimen is the optimal regimen? Should we give gemcitabine plus cisplatin or should we give this regimen called MVAC? Which is a four drug regimen with the MVAC being an acronym for the drugs that are used in that regimen. The VESPER study had an interesting and unusual design, but it was a practical design. And that is that at the time that the investigators designed the study, there was an equal amount of chemotherapy being given before cystectomy called neoadjuvant therapy as was being given after surgery called adjuvant chemotherapy in France.

And they weren’t quite sure if they designed a study just giving the treatment before surgery or just giving the treatment after surgery if they would be able to enroll a sufficient number of patients. So they made the decision to allow the treatment to be administered either in the neoadjuvant or adjuvant setting. That results in some complexities in terms of trial design, but it was a very practical decision. And it turns out that the vast majority of patients enrolled on this study received the treatment prior to surgery that is neoadjuvant therapy. And so the study really does address that important question, neoadjuvant gemcitabine plus cisplatin or neoadjuvant dose-dense MVAC?

Rick Bangs:

And there’s some history around these two chemotherapies in muscle invasive bladder cancer. So can you tell us a little bit about the history? MVAC was first, I think.

Dr. Matthew Galsky:

MVAC was developed first and the history of systemic therapy in bladder cancer and in particular, neoadjuvant systemic therapy is also unique and interesting. In that the regimens that have been proven to be effective in phase three clinical trials are actually not the regimens that are commonly used in the clinical setting over the past decade. And that’s for a number of reasons, which I’ll explain. So the MVAC regimen was developed in the late seventies, early eighties. Really, Dr. Allen Jagoda was credited for developing this regimen. Dr. Cora Sternberg published some of the initial papers on the regimen. Essentially, the investigators at the time took the four most active drugs that were available in bladder cancer and combined them together. And so that’s the four drugs in the MVAC regimen. Methotrexate, vinblastine, doxorubicin, and cisplatin, the names of the chemotherapy drugs.

When that regimen was initially developed, it resulted in shrinkages of metastatic cancer that were higher than what we had seen previously with other drugs or giving the drugs as single agents. And so that became a standard regimen. There were a series of phase three studies done enrolling individuals with metastatic cancer, comparing that four drug regimen to other regimens showing the four drug regimen was better. So that ultimately solidified its role as a standard of care. However, there was a downside and the downside was that there were a lot of side effects with the MVAC regimen, that was one. The other was, of course, there was always the desire to make treatment even better. And so Dr. Sternberg and colleagues sought to do that by modifying the MVAC regimen to try and make it both more effective and better tolerated.

And that was done by giving the regimen in what’s called a dose-dense fashion. Without going into the weeds too much, there was a theory based on mathematical modeling of growth kinetics of cancers that suggested that giving the same chemotherapy more frequently would actually work better. But in order to do that, one had to support the bone marrow to make new white blood cells because that was a limiting factor in giving chemotherapy more frequently. So this approach was developed called dose-dense chemotherapy, simply giving the same drugs but more frequently, but with what’s called growth factor support. This is a drug that stimulates the bone marrow to make new white blood cells so that the white blood cells don’t drop so low that you can’t administer the treatment because of the risk of infection.

So with that modification, treatment with MVAC became a little bit better and it became better tolerated. With that established at around the same time, another chemotherapy regimen was developed called gemcitabine and cisplatin. You’ll notice that the cisplatin is common between the two regimens. The gemcitabine is different. A phase three study was done with the old dosing of MVAC versus gemcitabine and cisplatin conducted by investigators including [inaudible 00:08:00] and colleagues published many years ago. And that showed that the regimens seemed to be pretty similar in individuals with metastatic bladder cancer, but gemcitabine cisplatin was better tolerated. And so that became a standard in the metastatic setting.

You’ll remember that that comparison was with the older way of administering MVAC. So with this dose-dense regimen established, investigators started to try and use that regimen in the neoadjuvant setting and showed in small clinical trials that it was pretty effective. Gemcitabine plus cisplatin though never tested in phase three studies as neoadjuvant therapy started to be used because it was a better tolerated regimen and that created this quandary. We had this two drug regimen that had never been formally tested in phase three clinical trials in the neoadjuvant setting, but was being used in the clinic. And we had this new way of administering MVAC, which made it safer and potentially more effective leading ultimately to the VESPER study.

Rick Bangs:

And so when we talk about phase three, we’re talking about a fairly large sample of patients. It’s got some level of rigor in it.

Dr. Matthew Galsky:

So phase three studies are generally randomized studies. So taking what’s considered a standard of care and comparing it against something new that’s hopefully better, maybe safer. And usually with definitive endpoints, meaning does the newer treatment lead to patients living longer, better? Ideally both.

Rick Bangs:

So we got some results and it seems like we have a winner and potentially a new standard of care. So what’s the conclusion?

Dr. Matthew Galsky:

So the VESPER study was a study that is incredibly important to the field. Really it’s the only phase three study seeking to address this question. But with any clinical trials, there are caveats. And one of the caveats of this trial is that it was designed 10 years ago, a little bit more. And it was designed with the best knowledge available at the time, but there are some limitations in terms of the generalizability of the results. So let me explain. The trial randomized 500 patients to receive either gemcitabine or cisplatin versus dose-dense MVAC as neoadjuvant therapy prior to cystectomy. As mentioned, the trial allowed patients to receive the treatment after surgery or 437 patients received it before. So 437 patients randomized in the neoadjuvant setting.

The primary endpoint of the study was progression-free survival at three years. So at three years, were more patients treated with one regimen versus the other without evidence of cancer coming back? That was essentially the endpoint. And then in the final analysis, they looked at overall survival. That is, were more patients alive at five years with one regimen or the other? We always look at eligibility criteria because eligibility criteria impacts the generalizability of results of a study. That is, are the patients in the real world the same as the patients who are treated in the clinical trial? And there’s one aspect to the VESPER study that does limit generalizability a bit, which is that they limited enrollment to patients who were younger than 80 years old.

But for reasons that aren’t entirely clear, there were no patients older than 69 enrolled in the study. We know that the median age of diagnosis of bladder cancer in the United States is 73. And so there are some issues in terms of potential generalizability of the results. The other potential impact of the design on generalizability is that the two regimens that were administered weren’t administered in the way that they’re commonly used in the clinic historically. That is, four cycles of gemcitabine plus cisplatin were administered, which is how we usually give the treatment. But six cycles of dose-dense MVAC was administered instead of four, which is commonly used in the clinic.

And so not only were the regimens different, but the number of cycles were different. And so the question ultimately becomes, is there a difference in the regimens or is just more chemotherapy better? So with those two caveats in mind, yes, the trial did show that there was an improvement in three-year progression-free survival with dose-dense MVAC versus gemcitabine and cisplatin. And then in this most recent analysis at five years, the overall survival was better with dose-dense MVAC versus gemcitabine and cisplatin. Some of these results that I just cited while statistically significant were not the primary endpoints of the study.

And so there is some limitation in terms of how definitive one can be about those conclusions. And that result in the context of some of the generalizability issues that I mentioned, I think makes us interpret the trial in the light that, yes, dose-dense MVAC is a good regimen in patients who are good candidates for it, and there’s solid data here. But if one can’t receive dose-dense MVAC then gemcitabine plus cisplatin is certainly a reasonable regimen.

Rick Bangs:

So if you’re one of those patients that was over 69 and sitting in front of you in the clinic, you would make a judgment and discuss with a patient the option specific to their situation and their medical condition. Right?

Dr. Matthew Galsky:

That’s correct. About 60% of patients in the VESPER study randomized to the dose-dense MVAC arm were able to receive all six cycles of treatment. So we know that there were some limitations in terms of being able to receive the full planned six cycles. I don’t know that any of my colleagues are transitioning to the six cycles of treatment based on the results of this study, particularly given the difficulty administering that full dosing regimen. The second issue is that some of the side effects were increased with dose-dense MVAC versus GemCis. So I think in a patient who didn’t completely meet the eligibility criteria for the study, certainly reasonable to discuss the risks versus benefits of each regimen. And I think either regimen is quite reasonable, more important that neoadjuvant chemotherapy is administered than probably which regimen is administered.

Rick Bangs:

All right. In 2023, how well can we mitigate side effects of these regimens?

Dr. Matthew Galsky:

So it depends a little bit on the side effect. And things like nausea and vomiting, I think we’ve done much better at the past 15 years or so with modern anti-nausea medications that are given prophylactically, that are given preventatively. Although it’s still quite heterogeneous from individual to individual. Fatigue tends to be cyclical with treatment and highly heterogeneous as well from individual to individual. There are things like risk for infections, which can certainly be mitigated, at least in part based on the use of growth factors with the dose-dense MVAC regimen to try and prevent white blood cells from dropping low. And incidentally, that also decreases the risk for mucositis inflammation of the mouth, the mucus membranes in the mouth and throat, or mouth soreness, et cetera.

Rick Bangs:

I see. So when would we expect the guidelines, whichever source of guidelines we use to reflect the change in the VESPER trial?

Dr. Matthew Galsky:

Guidelines typically are delayed a little bit until full study results are published. And then those involved in developing the guidelines can review the data and make a determination on the level of evidence based on the data, and then that impacts how strong the recommendation is made within the guidelines. So I think once we see the overall survival results published, we’ve seen them presented from the VESPER study but not published yet. I think once we see those overall survival results published, we’ll know how definitive those involved with making guidelines will be about this recommendation. My sense, based on the caveats that I mentioned, is that both regimens will be viewed as acceptable.

Rick Bangs:

All right. So just to get a little more clarity around what you just said. So if I go to my doctor and my doctor recommends GemCis, should I question it and should I find another doctor? I think I know the answer, but I want to hear you.

Dr. Matthew Galsky:

I think it’s certainly reasonable to ask about this other regimen, dose-dense MVAC. Why do you feel like I’m not a good candidate for that? I think that’s a fair question, but as mentioned, I think that either regimen is reasonable.

Rick Bangs:

Right, right. So is there additional work coming out of this trial? Because I know often these additional gifts that come as part of doing any clinical trial. So do we have additional work coming from the VESPER trial or other head-to-head chemo comparisons?

Dr. Matthew Galsky:

So there’s additional translational work going on with the VESPER study, and what that means is that there are investigations of the tumor specimens and blood and urine specimens that were obtained during the course of this study to determine perhaps which individuals are good candidates for one regimen versus the other. Of course, you know well the other study that was not designed to directly compare these regimens, but looked at an indirect comparison of the regimens with SWOG1314. And this study involved dose-dense MVAC or GemCis as well, and not designed to definitively compare those regimens as mentioned, but showed that they were pretty similar as well.

Rick Bangs:

So the long-term goal would be to know who should get chemo and what chemo they should get in advance of getting any chemo.

Dr. Matthew Galsky:

That’s exactly right.

Rick Bangs:

That’s the holy grail.

Dr. Matthew Galsky:

I was just going to say that the ultimate goal is both to determine who needs treatment and who benefits from treatment. And oftentimes these concepts are conflated, but they’re actually different concepts. We know that in the neoadjuvant setting, when we give chemotherapy prior to a surgical removal of the bladder, the goal of giving that chemotherapy is of course not to eradicate what’s in the bladder if the bladder’s going to be removed surgically. Of course, that’s a secondary goal, and there’s a lot of research going on around that particular question. But ultimately, the goal of neoadjuvant therapy is to eradicate microscopic spread of cancer. And we know not all patients have microscopic spread of cancer. So if we can develop tools to determine who needs treatment, who has microscopic spread of cancer, and then which treatments actually are able to eradicate that microscopic spread of cancer in individual patients. That’s when we’ll really achieve our goal of precision medicine.

Rick Bangs:

And I think a lot of patients think of the tumor in the bladder as the problem, and it’s just part of the problem. There’s more to it. There’s potential for spread outside the bladder. So that’s what we have to watch for, and that’s usually what I think kills people. Any other exciting work happening in the chemotherapy space for the initial treatment for a bladder cancer patient?

Dr. Matthew Galsky:

So the next wave of results that we’re going to see in the neoadjuvant setting in bladder cancer is whether or not we should be adding immunotherapy or more specifically, a class of drugs called immune checkpoint inhibitors. Those drugs have a role in metastatic bladder cancer. They’re now approved for treatment in the adjuvant setting. That is after cystectomy, after the bladder’s been removed, whether or not they should be removed. They should be removed even earlier to the neoadjuvant setting, such as giving chemotherapy with immunotherapy together. I think we’re going to have results from some of those studies fairly soon.

Rick Bangs:

Excellent. Any final thoughts as we wrap up?

Dr. Matthew Galsky:

I would say that the main final thought is that this is an incredibly important question that VESPER addressed. It highlights some of the difficulties conducting these large clinical trials that take a long time to complete. It provides very valuable data, but probably the most important is that if an individual can safely receive chemotherapy, that’s the most important that they receive neoadjuvant chemotherapy prior to surgery.

Rick Bangs:

Great. So Dr. Galsky, I want to thank you for helping us understand the results of the MVAC versus GemCis comparison trial. And that trial was called VESPER and what those results mean to the bladder cancer community. If you’d like more information about bladder cancer, please visit the BCAN website, www.bcan.org. In case people would like to get in touch with you, would you share your Twitter handle or any other information you’d like people to have?

Dr. Matthew Galsky:

Sure. Thanks. So my Twitter handle is @MattGalsky, @M-A-T-T-G-A-L-S-K-Y.

Rick Bangs:

Excellent. Thank you. Just a reminder, if you’d like more information about bladder cancer, you can contact the Bladder Cancer Advocacy Network at 1-888-901-2226. That’s all the time we have today. Be sure to like, comment and subscribe to this podcast so we have your feedback. Thank you for listening, and we’ll be back soon with another interesting episode of Bladder Cancer Matters. Thanks again, Dr. Galsky.

Dr. Matthew Galsky:

Thank you.

Voice over:

Thank you for listening to Bladder Cancer Matters, a podcast by the Bladder Cancer Advocacy Network or BCAN. BCAN works to increase public awareness about bladder cancer, advanced bladder cancer research, and provide educational and support services for bladder cancer patients. For more information about this podcast and additional information about bladder cancer, please visit bcan.org.